Editor’s Note: BCAction attended the San Antonio Breast Cancer Symposium in December 2013 to bring a patient-focused voice to the proceedings, to challenge the status quo, report findings back to you, and to push researchers and clinicians to do better for women at risk of and living with breast cancer. For Zoe Christopher’s reporting from SABCS on the often-overlooked psychosocial issues in breast cancer, click here.
By Karuna Jaggar, Executive Director
Report-Back on Aromatase Inhibitors
“The change from brand-name to generic aromatase inhibitors and hormone therapy adherence for early stage breast cancer.”
This study showed that 45% of breast cancer patients report that high drug costs often result in some form of “non-adherence,” meaning that patients are not taking prescribed treatments. Women who don’t take their prescribed treatments have lower survival rates. Not surprisingly, wealthier women (over $100,000) are more likely to be able to afford, and therefore take, their drugs than poorer women (less than $40K/yr). When the presenter compared the price of a one-month supply of everolimus ($9,416) vs. a one-month supply of anastrozole ($110), there were gasps across the large conference hall. This presentation underscored that patients must come before pharmaceutical industry profits.
“Randomized trial of exercise vs. usual care on aromatase inhibitor-associated arthralgias in women with breast cancer: The hormones and physical exercise (HOPE) study.”
This study explored exercise as a remedy for the very common side effects of aromatase inhibitors (AIs). The goal is that if exercise controls side effects, more women will take the treatments, and see improved outcomes. After one year of getting recommended levels of exercise, women taking aromatase inhibitors reported a 30% decrease in joint pain. (Recommended exercise = 2x weekly strength training and 2.5 hrs moderate intensity aerobic activity.) One limit of the study is that we don’t know if the benefits are due to aerobic exercise, resistance training, or the combined effect. A number of women chiming in with personal experience said that doing even light exercise like walking helps ease joint pain from taking AIs. How can we make sure all women, in all communities, are able to get the recommended levels of exercise? Social inequities lead to health disparities and we need to support findings on the benefits of exercise with systemic public health solutions.
“Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): An international, double-blind, randomized placebo-controlled trial.”
Researchers reported that taking the breast cancer drug anastrozole (sold as Arimidex) for five years reduced the chances of post-menopausal women at high risk of breast cancer developing the disease by 53% compared with women who took a placebo. This is the report from the IBIS 2 trial that included post-menopausal women who were at increased risk of breast cancer because of family history, DCIS or breast density. Median follow-up was five years. In the placebo arm of the trial, there was a 5.6% incidence of breast cancer (including DCIS) which was reduced by over 50% to 2.8% in the anastrozole arm of the trial.
Although this is a significant finding about anastrozole, the media headlines coming out about this research may overstate the actual significance (for example, the Chicago Tribune ran this story under the headline “Arimidex halves breast cancer risk, study finds”). For one thing, the actual numbers of women being followed are significant but still small. In addition, the absolute risk difference between placebo group and the anastrozole group was only a 2.8% difference, with no difference in mortality rates between the two groups. So we are really talking about risk reduction, not prevention. This is significant reduction in breast cancer risk, but we must be clear to women that it lowers risk by a few percentage points in what is already a low risk; for any one individual, it cannot be said it would prevent you from getting breast cancer.
Another point to note is that the researchers compared anastrozole only to a placebo group, not to a control group of women taking other aromatase inhibitors (AIs). This is concerning because the authors believe anastrozole should be the drug of choice. If this drug is going to be promoted as a replacement for other AIs, we want to know how anastrozole performs not just compared to a placebo but also as compared to the other two AIs that are currently the risk reduction drugs of choice. In other words, is this a better drug than what’s already in use, or just a newer (perhaps more expensive) drug?
Last, but certainly not least, the authors of this study seemed to downplay the drug’s side effects, focusing on the fact that women need to be educated about side effects as opposed to normal aches and pains of aging. This may make sense except for the fact that other studies (in fact, in the presentation immediately following this one) have shown that in the first year of use, up to 20-30% of women stop taking the drug because of the side effects, most commonly because of muscular and skeletal pain as well as depression, insomnia, fatigue, and cognitive issues.
The authors rightly acknowledge long term follow-up is needed. We would also like to see direct comparisions of anastrozole to other AIs so high-risk women know exactly what their choices are if they consider taking any AI.
Some Notes on “Basic Science”
I’ve taken to avoiding the sessions about so-called basic science, which is typically only comprehensible to the folks with expertise in that field—even other researchers and doctors struggle to follow. But there were two areas in basic science that were widely discussed at SABCS 2013. Here’s a quick summary.
Thirty years after widespread medical interest in immunotherapy, we still have not harnessed its potential but there were three papers on the topic at SABCS 2013. Lymphocytes are white blood cells that are part of the immune system. Research has shown that the more of these cells from the immune system (lymphocytes) are found in a tumor, the better the prognosis. A patient’s immune system appears to play an important role in chemo, targeted therapies, etc. although we do not yet know how to support the immune system and what interventions can increase the number of tumor-infiltrating lymphocytes.
Stem cells are cells that are able to self-renew and can create two equal cells. Researchers have found there are two types of stem cells in breast cancer: luminal and basal. Although just 1 in 1,000 cells in a tumor are stem cells, they are vitally important because stem cells are resistant to therapy and can regrow the entire tumor months, years, decades later. There has been suggestion from research in animals that a better indicator of prognosis than tumor progression is markers in the form of proteins that are expressed on these stem cells. Researchers’ interest in targeting stem cells in the future is reinforced by the finding that some stem cells over-express HER2, even in tumors that are not HER2+. The researcher presenting this information noted that a control group that didn’t have HER2 amplification also got significant benefit from that therapy and this may be an area of future investigation.
Updates on HER2+ Drug Trials
HER2+ breast cancers account for 20-30% of breast cancer diagnoses. There were some updates on HER2+ drug trials presented in years past, and researchers now have more mature data.
The first trial reported on, Neo-ALTTO, looks at whether adding Lapatinib to Trastuzumab (Herceptin) is beneficial to patients. Lapatanib is another HER2 antagonist. The study design asks whether the incremental gain in pathological complete response (pCR) observed with dual HER2 blockade translates into improved event-free survival (EFS) and overall survival (OS).
pCR means that the tumor has completely disappeared from the breast and lymph nodes. pCR is used as a surrogate endpoint after an Food and Drug Administration (FDA) meta-analysis showed that pCR is linked to longer overall survival. We have to be very careful with this approach which has not been shown to be true for ER+ cancers.
In the Neo-ALTTO study, presented by Dr. Martine Piccart-Gebhart, patients who achieved pCR had significantly better event-free survival and overall survival, irrespective of the treatment arm they were in. At approximately a four-year median follow-up, dual HER2 blockade appears to provide better pCR, EFS, and OS benefit for patients with HER2+ hormone-tumors. Overall survival was improved for patients experiencing pCR, with a 60% reduction in mortality. HR negative tumors are the greatest responders, but researchers didn’t see the same impact on ER+ with statistical significance. These are slower-growing tumors that can have late recurrences, so it’s possible they’ve not had enough time to see whether there is a similar benefit.
It is always important to balance potential benefit with safety analysis and quality of life for patients. The most commonly experienced side effects women include diarrhea, liver enzymes, and rash. One in four patients taking lapatinib in the trial experienced severe diarrhea and patients on the trastuzumab experienced significantly fewer side effects compared with those in the combination and Lapatinib arms. Indeed, only two thirds of patients were able to complete treatment of lapatinib in both phases. In contrast, 90% of patients on the trastuzumab completed their treatment in the neoadjuvant phase, with 80% completing the treatment in the adjuvant phase.
The second Her2+ study, TRIO-US B07, presented by Dr. Sarah Hurvitz, shared the final analysis of a Phase II three-arm randomized trial. This is only a Phase II trial (drugs don’t come to market until Phase III), so I won’t discuss this study other than to say I am pleased that there will be an analysis of patients who did not get pCR.
The third trial, the BETH trial, presented by Dr. Dennis Slamon, was a negative trial that failed to show any benefit to patients from adding Avastin (bevestuzumab) after surgery for HER2+ tumors. The study compared invasive disease-free survival in patients treated with chemo and Herceptin versus chemo and Herceptin with the addition of bevacizumab (Avastin). After 38 months, 92% of patients had disease-free survival for both trial arms—somewhat of a surprise that it was so high. The main difference was in cardiac adverse events, including hypertension—so based on this evidence there was no benefit for patients, just harm in adding Avastin.
The Best Treatment May Be Less Treatment
A couple of studies evaluated the provision of less treatment in an effort to reduce the harms of treatment. I took note of what Dr. Hyman Muss, (from the University of North Carolina at Chapel Hill) said: “the best therapy is not always the most therapy.”
The first study looked at older women with low risk tumors. This was from the Prime 2 trial and was presented by Dr. Ian Kunkler, professor of clinical oncology at the Edinburgh Cancer Research Center. The harms of radiation are well documented and this study evaluated whether older patients with more benign tumors might omit radiation and be spared the morbidity associated with radiation treatment. Data from women who were randomized to whole breast radiation or no breast radiation after lumpectomy showed that older women with low risk breast cancer (small hormone positive tumors) who did not receive radiation with a lumpectomy were no more likely to die of breast cancer than women who did receive radiation. Only 1% experienced metastasis and the majority of deaths were not from breast cancer.
While there is no difference in overall survival, radiation does reduce local recurrence of hormone positive breast cancer by 2.8% over 5 years: 1.3% compared to 4.1% recurrence for non-radiation. Receiving radiation upfront lowered the chance of the tumor growing back from 4% to 1% but there was no effect on survival.
Furthermore, for the relatively few women whose tumors do grow back, because they have not previously had radiation, they remain eligible for a second lumpectomy followed by radiation. In summary, this gives women (who fit the above criteria) a choice of having radiation that does not appear to compromise their survival.
Surgery for women with metastatic breast cancer was also addressed in the discussion about reduced treatment. Because metastatic cancer has spread beyond the breast, this surgery is sometimes referred to as “local control.” Dr. Seema Khan discussed data related to two studies (one from India and one from Turkey) evaluating the benefit of surgery for women with metastatic disease. There were some differences in the trial design between the two studies presented. Dr. Khan noted the difficulty of designing trials given the heterogeneity of metastatic cancer and the range of systemic therapies used. Despite these variations, the key finding of both studies was no difference in overall survival for women with metastatic cancer who did or did not have surgery to remove the breast tumor.
In addition to these two studies presented, there are four additional studies evaluating this same issue that are taking place around the world. When those studies are complete, we’ll need to reassess the current assumptions in light of any new data that emerges. Based on the studies presented at SABCS in 2013, surgery should not be offered to asymptomatic women with metastatic breast cancer.
Psychology and Survivorship
(For more information on this topic see the accompanying article in this issue by Zoë Christopher.)
Dr. Lesley Fallowfield (University of Sussex) works on psychology and survivorship issues. Originally a nurse before pursuing degree in experimental psychology, Fallowfield’s talk at SABCS (“Psychology/Survivorship Issues: Are we doing any better?”) was remarkable for her humor and humanity. Unlike so many people immersed in clinical trial data, rather than downplaying the effects of breast cancer diagnosis and treatment, she understands the “really horrible” nature of many side effects and takes seriously the question of “are we making progress?”
Fallowfield addressed two issues of survivorship: women who will go on to be cancer-free and women with metastatic disease (too often overlooked in survivorship discussions), who have equally important psychosocial needs. As more women are surviving their cancer diagnosis for longer periods, there is a growing community of women living with breast cancer.
But “nothing comes without a cost” notes Fallowfield—and the cost of both diagnosis and treatment is substantial. Even advancements in better radiation, more chemo options, a range of hormone treatments, and new targeted therapies all take a significant toll. And these physical effects of treatment are accompanied by important psychological, social and sexual effects. All of which can be acute and long-term. While many of these effects are documented, they are themselves not adequately managed. Furthermore, “few patients inhabit social vacuums and diagnosis and treatment affect everyone else in her social milieu.”
Anxiety and depression are common among women diagnosed with breast cancer. Approximately one-third of women are likely to have experienced one or both over the disease period. But, importantly notes Fallowfield, measures of anxiety and depression were developed for psychiatrically ill, rather than physically ill, patients.
Given the implications of a cancer diagnosis, anxiety is not surprising. Women face a real risk of recurrence and metastasis, even years after the initial diagnosis. Fallowfield argues that for this reason, understanding and managing anxiety ought to take account of the fact that women diagnosed with breast cancer are in fact facing potentially life-threatening disease. To date, non-pharmacological interventions (like yoga, art and music therapy, mindful-based stress reduction, cognitive behavior therapy, aromatherapy, massage, etc.) have ebbed and waned in popularity, with mixed and modest results.
Given my personal and professional experiences supporting women through breast cancer diagnoses, I was not at all surprised that 80% of patients referred to a counselor for anxiety actually had unmet informational needs about their diagnosis rather than psychological problems. As we know more about breast cancer (and more about what we don’t know), communication with patients has gotten more and more complex and the importance of patient information and decision aids is clear. Healthcare providers must ensure patients are truly educated and give informed consent—not an easy disease to explain with all the subtypes and advances in treatment options.
Fatigue has come to replace nausea and vomiting as the biggest post-cancer treatment problem and may last many years. To treat fatigue, Fallowfield argues, we must understand it. Interestingly, rest may not be the best remedy for fatigue. As several studies have shown, exercise improves mood state and fatigue, specifically aerobic exercise but not resistance training. For the debilitating problems associated with lymphedema, prevention is key. In the absence of good treatments, the onus is on surgeons to minimize the harm by doing sentinel node biopsy that dramatically reduces the rate of lymphedema from 20% to 5.6%.
The side effects of hormone therapy, vasomotor problems, and sexual problems that can occur from treatment are not just minor inconveniences—and they lead to women going off treatment. Each of these effects is often under-recognized; and if under-recognized, they are then under-reported, and as a result under-treated.
Almost three quarters of Australian women experienced sexual problems in the 2 years following diagnosis. Eighty-percent of those women claimed they had satisfying sex life prior to diagnosis. Moisturizers are better than lubricants for vaginal dryness. Seventy-seven percent of these Australian women reported hot flashes and night sweats. In terms of non-hormonal interventions, only relaxation decreased frequency and severity.
An effect of cancer diagnosis that is rarely addressed in forums like SABCS is the economic burden on women and their families. While there is some discussion of the high costs of treatments, the broader economic impact is rarely discussed. I was surprised to learn that many women don’t return to work and 10 months after surgery, that number is only 59%. With the caveat that I do not have access to her slides, I believe Dr. Fallowfield reported that the estimated economic loss for women and their families is $16,441 in the year of diagnosis and an additional $4,500/year thereafter.
I was so pleased that Dr. Fallowfield explicitly discussed what she called “survivorship” in metastatic breast cancer. Virtually all of survivorship focused on breast cancer neglects the issues in metastatic disease. Yet there are clear and unmet psychosocial needs. About half of women reported difficulty talking to others, and denying the severity of their illness to close friends and relatives. Inability to work presents major challenges and has a huge impact on families. Frequent medical appointments produce additional strains.
One area that is discussed is the physical and psychological impact of bone metastasis, which is often painful and not effectively treated. My own focus on inequities brings me to add that African American women are at particular risk for inadequate pain control, as research has shown their doctors are more likely to suspect drug dependency.
Dr. Fallowfield concluded by addressing the discomforts of treatment and the impact of time spent traveling to and from endless medical appointments as well as the time waiting to be seen. She discussed ways of changing treatment protocols to minimize this time as well as the discomfort of IV treatments.
After all, time is precious for all of us, whether we are living with metastatic cancer or not.